tbuckley/cabot-search huggingface dataset:
Mutant <i>KRAS</i> Mediates circARFGEF2 Biogenesis to Promote Lymphatic Metastasis of Pancreatic Ductal Adenocarcinoma
Authors: Yao Kong, Yuming Luo, Shangyou Zheng, Jiabin Yang, Dingwen Zhang, Yue Zhao, Hanhao Zheng, Mingjie An, Yan Lin, Le Ai, Xiayao Diao, Qing Lin, Changhao Chen, Rufu Chen
Journal: Cancer Research (2023)

Circular RNAs (circRNA) contribute to cancer stemness, proliferation, and metastasis. The biogenesis of circRNAs can be impacted by the genetic landscape of tumors. Herein, we identified a novel circRNA, circARFGEF2 (hsa_circ_0060665), which was upregulated in KRASG12D pancreatic ductal adenocarcinoma (PDAC) and positively associated with KRASG12D PDAC lymph node (LN) metastasis. CircARFGEF2 overexpression significantly facilitated KRASG12D PDAC LN metastasis in vitro and in vivo. Mechanistically, circARFGEF2 biogenesis in KRASG12D PDAC was significantly activated by the alternative splicing factor QKI-5, which recruited U2AF35 to facilitate spliceosome assembly. QKI-5 bound the QKI binding motifs and neighboring reverse complement sequence in intron 3 and 6 of ARFGEF2 pre-mRNA to facilitate circARFGEF2 biogenesis. CircARFGEF2 sponged miR-1205 and promoted the activation of JAK2, which phosphorylated STAT3 to trigger KRASG12D PDAC lymphangiogenesis and LN metastasis. Importantly, circARFGEF2 silencing significantly inhibited LN metastasis in the KrasG12D/+Trp53R172H/+Pdx-1-Cre (KPC) mouse PDAC model. These findings provide insight into the mechanism and metastasis-promoting function of mutant KRAS-mediated circRNA biogenesis.
Associations between AI-Assisted Tumor Amphiregulin and Epiregulin IHC and Outcomes from Anti-EGFR Therapy in the Routine Management of Metastatic Colorectal Cancer
Authors: Christopher J.M. Williams, Faye Elliott, Nancy Sapanara, Faranak Aghaei, Liping Zhang, Andrea Muranyi, Dongyao Yan, Isaac Bai, Zuo Zhao, Michael Shires, Henry M. Wood, Susan D. Richman, Gemma Hemmings, Michael Hale, Daniel Bottomley, Leanne Galvin, Caroline Cartlidge, Sarah Dance, Chris M. Bacon, Laura Mansfield, Kathe Young-Zvandasara, Ajay Sudan, Katy Lambert, Irena Bibby, Sarah E. Coupland, Amir Montazeri, Natalie Kipling, Kathryn Hughes, Simon S. Cross, Alice Dewdney, Leanne Pheasey, Cathryn Leng, Tatenda Gochera, D. Chas Mangham, Mark Saunders, Martin Pritchard, Helen Stott, Abhik Mukherjee, Mohammad Ilyas, Rafael Silverman, Georgina Hyland, Declan Sculthorpe, Kirsty Thornton, Imogen Gould, Ann O'Callaghan, Nicholas Brown, Samantha Turnbull, Lisa Shaw, Matthew T. Seymour, Nicholas P. West, Jenny F. Seligmann, Shalini Singh, Kandavel Shanmugam, Philip Quirke
Journal: Clinical Cancer Research (2023)

Abstract Purpose: High tumor production of the EGFR ligands, amphiregulin (AREG) and epiregulin (EREG), predicted benefit from anti-EGFR therapy for metastatic colorectal cancer (mCRC) in a retrospective analysis of clinical trial data. Here, AREG/EREG IHC was analyzed in a cohort of patients who received anti-EGFR therapy as part of routine care, including key clinical contexts not investigated in the previous analysis. Experimental Design: Patients who received panitumumab or cetuximab ± chemotherapy for treatment of RAS wild-type mCRC at eight UK cancer centers were eligible. Archival formalin-fixed paraffin-embedded tumor tissue was analyzed for AREG and EREG IHC in six regional laboratories using previously developed artificial intelligence technologies. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Results: A total of 494 of 541 patients (91.3%) had adequate tissue for analysis. A total of 45 were excluded after central extended RAS testing, leaving 449 patients in the primary analysis population. After adjustment for additional prognostic factors, high AREG/EREG expression (n = 360; 80.2%) was associated with significantly prolonged PFS [median: 8.5 vs. 4.4 months; HR, 0.73; 95% confidence interval (CI), 0.56–0.95; P = 0.02] and OS [median: 16.4 vs. 8.9 months; HR, 0.66 95% CI, 0.50–0.86; P = 0.002]. The significant OS benefit was maintained among patients with right primary tumor location (PTL), those receiving cetuximab or panitumumab, those with an oxaliplatin- or irinotecan-based chemotherapy backbone, and those with tumor tissue obtained by biopsy or surgical resection. Conclusions: High tumor AREG/EREG expression was associated with superior survival outcomes from anti-EGFR therapy in mCRC, including in right PTL disease. AREG/EREG IHC assessment could aid therapeutic decisions in routine practice. See related commentary by Randon and Pietrantonio, p. 4021
Safety and Efficacy of Tucatinib, Letrozole, and Palbociclib in Patients with Previously Treated HR+/HER2+ Breast Cancer
Authors: Elena Shagisultanova, William Gradishar, Ursa Brown-Glaberman, Pavani Chalasani, Andrew J. Brenner, Alison Stopeck, Hannah Parris, Dexiang Gao, Tessa McSpadden, Jose Mayordomo, Jennifer R. Diamond, Peter Kabos, Virginia F. Borges
Journal: Clinical Cancer Research (2023)

Abstract Purpose: To overcome resistance to antihormonal and HER2-targeted agents mediated by cyclin D1-CDK4/6 complex, we proposed an oral combination of the HER2 inhibitor tucatinib, aromatase inhibitor letrozole, and CDK4/6 inhibitor palbociclib (TLP combination) for treatment of HR+/HER2+ metastatic breast cancer (MBC). Patients and Methods: Phase Ib/II TLP trial (NCT03054363) enrolled patients with HR+/HER2+ MBC treated with ≥2 HER2-targeted agents. The phase Ib primary endpoint was safety of the regimen evaluated by NCI CTCAE version 4.3. The phase II primary endpoint was efficacy by median progression-free survival (mPFS). Results: Forty-two women ages 22 to 81 years were enrolled. Patients received a median of two lines of therapy in the metastatic setting, 71.4% had visceral disease, 35.7% had CNS disease. The most common treatment-emergent adverse events (AE) of grade ≥3 were neutropenia (64.3%), leukopenia (23.8%), diarrhea (19.0%), and fatigue (14.3%). Tucatinib increased AUC10–19 hours of palbociclib 1.7-fold, requiring palbociclib dose reduction from 125 to 75 mg daily. In 40 response-evaluable patients, mPFS was 8.4 months, with similar mPFS in non-CNS and CNS cohorts (10.0 months vs. 8.2 months; P = 0.9). Overall response rate was 44.5%, median duration of response was 13.9 months, and clinical benefit rate was 70.4%; 60% of patients were on treatment for ≥6 months, 25% for ≥1 year, and 10% for ≥2 years. In the CNS cohort, 26.6% of patients remained on study for ≥1 year. Conclusions: TLP combination was safe and tolerable. AEs were expected and manageable with supportive therapy and dose reductions. TLP showed excellent efficacy for an all-oral chemotherapy-free regimen warranting further testing. See related commentary by Huppert and Rugo, p. 4993
Phase I Study of Acalabrutinib Plus Danvatirsen (AZD9150) in Relapsed/Refractory Diffuse Large B-Cell Lymphoma Including Circulating Tumor DNA Biomarker Assessment
Authors: Mark Roschewski, Manish R. Patel, Patrick M. Reagan, Nakhle S. Saba, Graham P. Collins, Hendrik-Tobias Arkenau, Sven de Vos, Barrett Nuttall, Melih Acar, Kathleen Burke, Rafael D. White, Maria Udriste, Shringi Sharma, Brian Dougherty, Daniel Stetson, David Jenkins, Andrew Mortlock, Alessandra Forcina, Veerendra Munugalavadla, Ian Flinn
Journal: Clinical Cancer Research (2023)

Novel targeted and immunotherapies have improved outcomes in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), but toxicities limit widespread use. The selective Bruton tyrosine kinase (BTK) inhibitor acalabrutinib has activity in patients with R/R DLBCL but durable responses are uncommon. STAT3 inhibition has demonstrated clinical activity in DLBCL.Final results of the phase I study of acalabrutinib plus STAT3 inhibitor (danvatirsen; AZD9150) in patients with R/R DLBCL are reported. Danvatirsen 200 mg intravenous infusion [Days 1, 3, 5 (Cycle 1); weekly infusions starting Day 8, Cycle 1] was administered in combination with oral acalabrutinib 100 mg twice daily until progressive disease (PD) or unacceptable toxicity. Primary endpoints were safety and tolerability. Secondary endpoints included efficacy, pharmacokinetics, and immunogenicity.Seventeen patients received combination treatment. One dose-limiting toxicity (Grade 3 liver transaminase) occurred in 1 patient. The most common reason for treatment discontinuation was PD (65%). In evaluable patients (n = 17), objective response rate was 24%; median duration of response was 1.9 months. All responders with available DLBCL cell-of-origin data were either activated B-cell or nongerminal center B-cell like subtype. Genetic subtype did not correlate with response. Baseline and longitudinal plasma cell-free DNA (cfDNA) concentrations were mostly higher in nonresponding patients. cfDNA changes were generally concordant with imaging. Pretreatment circulating B-cell levels were higher in responders versus nonresponders.Targeting both STAT3 and BTK in combination is safe and tolerable but efficacy is limited in R/R DLBCL. Results support evaluation of circulating tumor DNA as a biomarker for clinical response.
Non-alcoholic fatty liver disease: pathophysiological concepts and treatment options
Authors: Christoph Grander, Felix Grabherr, Herbert Tilg
Journal: Cardiovascular Research (2023)

Abstract The prevalence of non-alcoholic fatty liver disease (NAFLD) is continually increasing due to the global obesity epidemic. NAFLD comprises a systemic metabolic disease accompanied frequently by insulin resistance and hepatic and systemic inflammation. Whereas simple hepatic steatosis is the most common disease manifestation, a more progressive disease course characterized by liver fibrosis and inflammation (i.e. non-alcoholic steatohepatitis) is present in 10–20% of affected individuals. NAFLD furthermore progresses in a substantial number of patients towards liver cirrhosis and hepatocellular carcinoma. Whereas this disease now affects almost 25% of the world’s population and is mainly observed in obesity and type 2 diabetes, NAFLD also affects lean individuals. Pathophysiology involves lipotoxicity, hepatic immune disturbances accompanied by hepatic insulin resistance, a gut dysbiosis, and commonly hepatic and systemic insulin resistance defining this disorder a prototypic systemic metabolic disorder. Not surprisingly many affected patients have other disease manifestations, and indeed cardiovascular disease, chronic kidney disease, and extrahepatic malignancies are all contributing substantially to patient outcome. Weight loss and lifestyle change reflect the cornerstone of treatment, and several medical treatment options are currently under investigation. The most promising treatment strategies include glucagon-like peptide 1 receptor antagonists, sodium–glucose transporter 2 inhibitors, Fibroblast Growth Factor analogues, Farnesoid X receptor agonists, and peroxisome proliferator–activated receptor agonists. Here, we review epidemiology, pathophysiology, and therapeutic options for NAFLD.
Black Phosphorus Nanosheets Assist Nanoerythrosomes for Efficient mRNA Vaccine Delivery and Immune Activation
Authors: Lixin Yang, Tengqi Wang, Dexin Zhang, Xin Huang, Yuqin Dong, Wen Gao, Youqing Ye, Ke Ren, Wei Zhao, Haishi Qiao, Lizhou Jia
Journal: Advanced Healthcare Materials (2023)

Messenger RNA (mRNA)-based vaccines have enormous potential in infectious disease prevention and tumor neoantigen application. However, developing an advanced delivery system for efficient mRNA delivery and intracellular release for protein translation remains a challenge. Herein, a biocompatible biomimetic system is designed using red blood cell-derived nanoerythrosomes (NER) and black phosphorus nanosheets (BP) for mRNA delivery. BP is covalently modified with polyethyleneimine (PEI), serving as a core to efficiently condense mRNA via electrostatic interactions. To facilitate the spleen targeting of the mRNA-loaded BP (BPmRNA ), NER is co-extruded with BPmRNA to construct a stable "core-shell" nanovaccine (NER@BPmRNA ). The mRNA nanovaccine exhibits efficient protein expression and immune activation via BP-mediated adjuvant effect and enhanced lysosomal escape. In vivo evaluation demonstrates that the system delivery of mRNA encoding coronavirus receptor-binding domain (RBD) significantly increases the antibody titer and pseudovirus neutralization effect compared with that of NER without BP assistance. Furthermore, the mRNA extracted from mouse melanoma tissues is utilized to simulate tumor neoantigen delivered by NER@BPmRNA . In the vaccinated mice, BP-assisted NER for the delivery of melanoma mRNA can induce more antibodies that specifically recognize tumor antigens. Thus, BP-assisted NER can serve as a safe and effective delivery vehicle in mRNA-based therapy.
Efficacy and Quality-of-Life Following Involved Nodal Radiotherapy for Head and Neck Squamous Cell Carcinoma: The INRT-AIR Phase II Clinical Trial
Authors: David J. Sher, Dominic H. Moon, Dat Vo, Jing Wang, Liyuan Chen, Michael Dohopolski, Randall Hughes, Baran D. Sumer, Chul Ahn, Vladimir Avkshtol
Journal: Clinical Cancer Research (2023)

Elective neck irradiation (ENI) has long been considered mandatory when treating head and neck squamous cell carcinoma (HNSCC) with definitive radiotherapy, but it is associated with significant dose to normal organs-at-risk (OAR). In this prospective phase II study, we investigated the efficacy and tolerability of eliminating ENI and strictly treating involved and suspicious lymph nodes (LN) with intensity-modulated radiotherapy.Patients with newly diagnosed HNSCC of the oropharynx, larynx, and hypopharynx were eligible for enrollment. Each LN was characterized as involved or suspicious based on radiologic criteria and an in-house artificial intelligence (AI)-based classification model. Gross disease received 70 Gray (Gy) in 35 fractions and suspicious LNs were treated with 66.5 Gy, without ENI. The primary endpoint was solitary elective volume recurrence, with secondary endpoints including patterns-of-failure and patient-reported outcomes.Sixty-seven patients were enrolled, with 18 larynx/hypopharynx and 49 oropharynx cancer. With a median follow-up of 33.4 months, the 2-year risk of solitary elective nodal recurrence was 0%. Gastrostomy tubes were placed in 14 (21%), with median removal after 2.9 months for disease-free patients; no disease-free patient is chronically dependent. Grade I/II dermatitis was seen in 90%/10%. There was no significant decline in composite MD Anderson Dysphagia Index scores after treatment, with means of 89.1 and 92.6 at 12 and 24 months, respectively.These results suggest that eliminating ENI is oncologically sound for HNSCC, with highly favorable quality-of-life outcomes. Additional prospective studies are needed to support this promising paradigm before implementation in any nontrial setting.
Genomic Profiling of Metastatic Castration-Resistant Prostate Cancer Samples Resistant to Androgen Receptor Pathway Inhibitors
Authors: Naoual Menssouri, Loïc Poiraudeau, Carole Helissey, Ludovic Bigot, Jonathan Sabio, Tony Ibrahim, Cédric Pobel, Claudio Nicotra, Maud Ngo-Camus, Ludovic Lacroix, Etienne Rouleau, Lambros Tselikas, Anne Chauchereau, Félix Blanc-Durand, Alice Bernard-Tessier, Anna Patrikidou, Natacha Naoun, Ronan Flippot, Emeline Colomba, Alina Fuerea, Laurence Albiges, Pernelle Lavaud, Paul van de Wiel, Eveline den Biezen, Yvonne Wesseling-Rozendaal, Santiago Ponce, Stefan Michiels, Christophe Massard, Daniel Gautheret, Fabrice Barlesi, Fabrice André, Benjamin Besse, Jean-Yves Scoazec, Luc Friboulet, Karim Fizazi, Yohann Loriot
Journal: Clinical Cancer Research (2023)

The androgen receptor axis inhibitors (ARPI; e.g., enzalutamide, abiraterone acetate) are administered in daily practice for men with metastatic castration-resistant prostate cancer (mCRPC). However, not all patients respond, and mechanisms of both primary and acquired resistance remain largely unknown.In the prospective trial MATCH-R (NCT02517892), 59 patients with mCRPC underwent whole-exome sequencing (WES) and/or RNA sequencing (RNA-seq) of samples collected before starting ARPI. Also, 18 patients with mCRPC underwent biopsy at time of resistance. The objectives were to identify genomic alterations associated with resistance to ARPIs as well as to describe clonal evolution. Associations of genomic and transcriptomic alterations with primary resistance were determined using Wilcoxon and Fisher exact tests.WES analysis indicated that no single-gene genomic alterations were strongly associated with primary resistance. RNA-seq analysis showed that androgen receptor (AR) gene alterations and expression levels were similar between responders and nonresponders. RNA-based pathway analysis found that patients with primary resistance had a higher Hedgehog pathway score, a lower AR pathway score and a lower NOTCH pathway score than patients with a response. Subclonal evolution and acquisition of new alterations in AR-related genes or neuroendocrine differentiation are associated with acquired resistance. ARPIs do not induce significant changes in the tumor transcriptome of most patients; however, programs associated with cell proliferation are enriched in resistant samples.Low AR activity, activation of stemness programs, and Hedgehog pathway were associated with primary ARPIs' resistance, whereas most acquired resistance was associated with subclonal evolution, AR-related events, and neuroendocrine differentiation. See related commentary by Slovin, p. 4323.
The room where it happens: addressing diversity, equity, and inclusion in National Clinical Trials Network clinical trial leadership
Authors: Rebecca A Snyder, Barbara Burtness, May Cho, Jaydira Del Rivero, Deborah B Doroshow, Kathryn E Hitchcock, Aparna Kalyan, Christina A Kim, Jelena Lukovic, Aparna R Parikh, Nina N Sanford, Bhuminder Singh, Chan Shen, Rachna T Shroff, Namrata Vijayvergia, Karyn A Goodman, Pamela L Kunz
Journal: JNCI Journal of the National Cancer Institute (2023)

Abstract Many multicenter randomized clinical trials in oncology are conducted through the National Clinical Trials Network (NCTN), an organization consisting of 5 cooperative groups. These groups are made up of multidisciplinary investigators who work collaboratively to conduct trials that test novel therapies and establish best practice for cancer care. Unfortunately, disparities in clinical trial leadership are evident. To examine the current state of diversity, equity, and inclusion across the NCTN, an independent NCTN Task Force for Diversity in Gastrointestinal Oncology was established in 2021, the efforts of which serve as the platform for this commentary. The task force sought to assess existing data on demographics and policies across NCTN groups. Differences in infrastructure and policies were identified across groups as well as a general lack of data regarding the composition of group membership and leadership. In the context of growing momentum around diversity, equity, and inclusion in cancer research, the National Cancer Institute established the Equity and Inclusion Program, which is working to establish benchmark data regarding diversity of representation within the NCTN groups. Pending these data, additional efforts are recommended to address diversity within the NCTN, including standardizing membership, leadership, and publication processes; ensuring diversity of representation across scientific and steering committees; and providing mentorship and training opportunities for women and individuals from underrepresented groups. Intentional and focused efforts are necessary to ensure diversity in clinical trial leadership and to encourage design of trials that are inclusive and representative of the broad population of patients with cancer in the United States.
Time-Restricted Eating Without Calorie Counting for Weight Loss in a Racially Diverse Population
Authors: Shuhao Lin, Sofia Cienfuegos, Mark Ezpeleta, Kelsey Gabel, Vasiliki Pavlou, Andrea Mulas, Kaitie Chakos, Mara McStay, Jackie Wu, Lisa Tussing-Humphreys, Shaina J. Alexandria, Julienne Sanchez, Terry Unterman, Krista A. Varady
Journal: Annals of Internal Medicine (2023)

Time-restricted eating (TRE), without calorie counting, has become a popular weight loss strategy, yet long-term randomized trials evaluating its efficacy are limited.
Trastuzumab Combined With Ramucirumab and Paclitaxel in Patients With Previously Treated Human Epidermal Growth Factor Receptor 2–Positive Advanced Gastric or Gastroesophageal Junction Cancer
Authors: Chang Gon Kim, Minkyu Jung, Hyo Song Kim, Choong-kun Lee, Hei-Cheul Jeung, Dong-Hoe Koo, Woo Kyun Bae, Dae Young Zang, Bum Jun Kim, Hyunki Kim, Un-Jung Yun, Jingmin Che, Sejung Park, Tae Soo Kim, Woo Sun Kwon, Juin Park, Sang Woo Cho, Chung Mo Nam, Hyun Cheol Chung, Sun Young Rha
Journal: Journal of Clinical Oncology (2023)

Trastuzumab-containing chemotherapy is the recommended first-line regimen for human epidermal growth factor receptor 2 (HER2)-positive advanced gastric or gastroesophageal junction (G/GEJ) cancer. We evaluated the safety and efficacy of trastuzumab combined with ramucirumab and paclitaxel as second-line treatment for HER2-positive G/GEJ cancer.Patients with HER2-positive advanced G/GEJ cancer who progressed after first-line treatment with trastuzumab-containing chemotherapy were enrolled from five centers in the Republic of Korea. Patients were administered a 28-day cycle of trastuzumab (once on days 1, 8, 15, and 22: 2 mg/kg followed by 4 mg/kg loading dose), ramucirumab (once on days 1 and 15: 8 mg/kg), and paclitaxel (once on days 1, 8, and 15: dose level 1, 80 mg/m2; or dose level -1, 70 mg/m2). Phase II was conducted with the recommended phase II dose (RP2D). Primary end points were determination of RP2D during phase Ib and investigator-assessed progression-free survival (PFS) in patients treated with RP2D.Dose-limiting toxicity at dose level 1 was not documented during phase Ib, and a full dose combination was selected as the RP2D. Among 50 patients with a median follow-up duration of 27.5 months (95% CI, 17.4 to 37.6), median PFS and overall survival were 7.1 months (95% CI, 4.8 to 9.4) and 13.6 months (95% CI, 9.4 to 17.7), respectively. Objective response rate was 54% (27 of 50, including one complete response), and disease control rate was 96% (48 of 50). Loss of HER2 expression was observed in 34.8% (8 of 23) patients after first-line treatment, and no definite association between HER2 expression and the outcome was revealed. Safety profiles were consistent with previous reports.Trastuzumab combined with ramucirumab and paclitaxel showed appreciable efficacy with manageable safety profiles in patients with previously treated HER2-positive G/GEJ cancer.
Annals Graphic Medicine - Dependence
Authors: Brian Smith
Journal: Annals of Internal Medicine (2023)

Web ExclusivesJuly 2023Annals Graphic Medicine - DependenceFREEBrian SmithBrian SmithStanford University School of Medicine, Stanford, California (B.S.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/G22-0051 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Download figure Download PowerPoint Download figure Download PowerPoint Download figure Download PowerPoint Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAuthors: Brian SmithAffiliations: Stanford University School of Medicine, Stanford, California (B.S.)Disclosures: The author has reported no disclosures of interest. The form can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=G22-0051.Author/Illustrator Information: Brian Smith is a second-year medical student at the Stanford University School of Medicine. For more of his work, please visit https://orcid.org/0000-0002-2075-6417 (e-mail, bsmith19@stanford.edu).This article was published at Annals.org on 27 June 2023. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Current IssueJuly 2023Volume 176, Issue 7 ePublished: 27 June 2023 Issue Published: July 2023 Copyright & PermissionsCopyright © 2023 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...